title: Cigarette smoke induces molecular responses in respiratory tissues of ApoE(-/-) mice that are progressively deactivated upon cessation.
abstract: Cigarette smoking is the primary etiology of chronic obstructive pulmonary disease (COPD) and a risk factor for both lung and cardiovascular (CV) diseases, which are rarely investigated concomitantly. Although smoking cessation shows clear CV risk benefit, lung-related disease risk remains higher in former smokers than in never smokers. We sought to determine the differential molecular responses of murine respiratory tissues to better understand the toxicity pathways involved in smoking-related disease risk and those related to the benefits of smoking cessation. ApoE(-/-) mice were exposed to mainstream cigarette smoke (CS) or a smoking cessation-mimicking protocol for up to 6 months and transcriptomics analysis of nasal epithelium and lung parenchyma performed. We supported our gene expression profiling approach with standard lung histopathology and bronchoalveolar lavage fluid (BALF) analysis. Many BALF analytes involved in functions ranging from inflammation to cell proliferation and tissue remodeling were found elevated in BALF. Gene expression levels of these molecules were also increased in lung tissue, suggesting that the inflammatory response was the result of local tissue activation and the contribution of recruited inflammatory cells. Gene set enrichment analysis (GSEA) of expression data from murine lungs and nasal epithelium showed distinct activation patterns of inflammation, complement, and xenobiotic metabolism pathways during CS exposure that were deactivated upon smoking cessation. Pathways involved in cell proliferation and tissue remodeling were activated by CS and progressively deactivated upon smoke exposure cessation. Differential CS-mediated responses of pulmonary and nasal tissues reflect common mechanisms but also the varying degrees of epithelial functional specialization and exposure along the respiratory tract.
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland. Electronic address: Stephanie.Boue@pmi.com.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boué
authors.forename: Héctor
authors.initials: H
authors.lastname: De León
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schlage
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Peck
authors.forename: Horst
authors.initials: H
authors.lastname: Weiler
authors.forename: An
authors.initials: A
authors.lastname: Berges
authors.forename: Grégory
authors.initials: G
authors.lastname: Vuillaume
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.forename: Baerbel
authors.initials: B
authors.lastname: Friedrichs
authors.forename: Stefan
authors.initials: S
authors.lastname: Lebrun
authors.forename: Kris
authors.initials: K
authors.lastname: Meurrens
authors.forename: Nadine
authors.initials: N
authors.lastname: Schracke
authors.forename: Michaela
authors.initials: M
authors.lastname: Moehring
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Steffen
authors.forename: Jutta
authors.initials: J
authors.lastname: Schueller
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanscheeuwijck
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D015415:Biomarkers; D001992:Bronchoalveolar Lavage Fluid; D003713:Dendritic Cells / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009538:Nicotine / Q000378:metabolism / Q000652:urine; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020545:Respiratory Mucosa / Q000473:pathology; D012137:Respiratory System / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects* / Q000473:pathology; D016540:Smoking Cessation; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D059467:Transcriptome
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D014028:Tobacco Smoke Pollution; D012313:RNA; D009538:Nicotine
keywords: ApoE(−/−) mice; BALF; Genome-wide expression; Inflammation; Smoking; Smoking cessation